The development of a safe, effective acceptable topical microbicide to prevent the sexual transmission of HIV-1 could play a major role in worldwide reduction of the over 14,000 new HIV-1 infections per day, and potentially save millions of lives. We obtained several lines of evidence suggesting that HIV-1 exploits syndecan-1 and -2 to successfully cross the genital epithelium. Thus, syndecans represent new targets for the development of topical microbicides. We propose to develop compounds that prevent HIV-1-syndecan interactions, both in vitro (R21 phase) and in vivo (the R33 phase). Specifically, we propose to develop and test compounds that neutralize either the mucosal syndecans (syndecan antagonists) or the syndecan-binding of HIV-1, gp120 (syndecan agonists). Importantly, we already generated a couple of syndecan antagonists and agonists, which efficiently prevent the passage of HIV-1 through primary human genital epithelial cells, further emphasizing that syndecans represent attractive targets for the development of microbicides. Since compounds that interrupt gp120-syndecan interactions have never been exploited as microbicides, they represent a novel class of microbicides and thus differ from existing tools. One advantage of using compounds, which target gp120-syndecan interactions as microbicides, is that all primary R5, X4 and R5X4 HIV-1 as well as HIV-2 isolates bind syndecans. Thus, these compounds will have a broader impact than, for example, RANTES derivatives, which neutralize R5 viruses only. Since we found that compounds that block gp120-syndecan interactions also block gp120-CCR5 interactions, their dual inhibitory effects represent another advantage of using them as microbicides. Moreover, another advantage of using microbicides that target syndecans is that many sexually transmitted pathogens also exploit syndecans for host colonization such as herpes simplex virus and Neisseria gonorrhoeae. Thus, microbicides targeting gp120-syndecan interactions will exhibit a broad inhibitory spectrum against sexually transmitted pathogens. [unreadable] [unreadable] [unreadable]